Effects of Inhibiting Early Inflammation in Kidney Transplant Patients

NCT ID: NCT02495077

Last Updated: 2022-08-16

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

290 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-11-02

Study Completion Date

2021-07-23

Brief Summary

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During transplant surgery, there is a period of time when a donated kidney is removed from a donor's body and stored until the time of the transplant surgery. The storage procedure results in buildup of various proteins within the kidney that can injure the donated kidney after it is transplanted. One of these proteins is tumor necrosis factor-alpha (TNF-alpha).

The purpose of this study is to evaluate whether taking infliximab, which blocks tumor necrosis factor alpha (TNF-alpha), just prior to transplant surgery, along with usual transplant medicines will protect the donated kidney from damage caused by TNF-alpha and help keep the transplanted kidney healthy for a longer period of time.

Detailed Description

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This is a Phase 2, multicenter, randomized, double blind (masked), placebo-controlled, 2-arm clinical trial of 300 deceased donor kidney transplant recipients. Participants will be randomized (1:1) to the experimental or control arm (150 subjects per arm).

Conditions

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Kidney Transplant

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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Experimental

rATG is co-administered with anti-TNFa (infliximab/Remicade®) plus maintenance therapy with tacrolimus, a mycophenolic acid derivative (either MMF or enteric coated MPA) and prednisone.

Group Type EXPERIMENTAL

Infliximab

Intervention Type BIOLOGICAL

A single dose, of 3mg/kg infusion

Methylprednisolone

Intervention Type DRUG

500mg will be Initiated just prior to or at the initiation of transplant surgery and prior to Infliximab and thymoglobulin infusion

Mycophenolate Mofetil

Intervention Type DRUG

Administered at a target dose of 2000mg daily, as tolerated, until study closure

Tacrolimus

Intervention Type DRUG

Administered at a target dose of 0.1mg/kg BID, post-op, then adjusted to target trough levels of 8-12ng/ml during 1st 3-months post-op and finally adjusted to target trough levels of 5-8ng/ml until study closure

Thymoglobulin®

Intervention Type BIOLOGICAL

Administered daily for 5 days with the intention of achieving a total dose of 4.5 to 6.0 mg/kg, as tolerated

Acetaminophen

Intervention Type DRUG

30 to 60 minutes prior to the start of the infusion

* Tylenol, 600 to 1000mg by mouth or
* Suppository form

Loratadine

Intervention Type DRUG

30 to 60 minutes prior to the start of the infusion

* Claritin (Loratadine) 10mg by mouth or
* Benadryl (Diphenhydramine) 25 or 50 mg by mouth

Prednisone

Intervention Type DRUG

Prednisone will be administered peri-operatively according to center practice. Prednisone should be gradually tapered to no less than 5 mg/day or 10 mg every other day by 3 months post-transplant thereafter until study closure.

Diphenhydramine

Intervention Type DRUG

30 to 60 minutes prior to the start of the infusion

* Claritin (Loratadine) 10mg by mouth or
* Benadryl (Diphenhydramine) 25 or 50 mg by mouth

Control

Rabbit anti-thymocyte globulin (rATG/Thymoglobulin®) plus placebo (Sterile normal saline) induction followed by maintenance therapy with tacrolimus, a mycophenolic acid derivative (either MMF or enteric coated MPA) and prednisone.

Group Type ACTIVE_COMPARATOR

Methylprednisolone

Intervention Type DRUG

500mg will be Initiated just prior to or at the initiation of transplant surgery and prior to Infliximab and thymoglobulin infusion

Mycophenolate Mofetil

Intervention Type DRUG

Administered at a target dose of 2000mg daily, as tolerated, until study closure

Tacrolimus

Intervention Type DRUG

Administered at a target dose of 0.1mg/kg BID, post-op, then adjusted to target trough levels of 8-12ng/ml during 1st 3-months post-op and finally adjusted to target trough levels of 5-8ng/ml until study closure

Thymoglobulin®

Intervention Type BIOLOGICAL

Administered daily for 5 days with the intention of achieving a total dose of 4.5 to 6.0 mg/kg, as tolerated

Acetaminophen

Intervention Type DRUG

30 to 60 minutes prior to the start of the infusion

* Tylenol, 600 to 1000mg by mouth or
* Suppository form

Loratadine

Intervention Type DRUG

30 to 60 minutes prior to the start of the infusion

* Claritin (Loratadine) 10mg by mouth or
* Benadryl (Diphenhydramine) 25 or 50 mg by mouth

Placebo for Infliximab

Intervention Type BIOLOGICAL

A single dose is volume matched to Infliximab (250mL) infusion

Prednisone

Intervention Type DRUG

Prednisone will be administered peri-operatively according to center practice. Prednisone should be gradually tapered to no less than 5 mg/day or 10 mg every other day by 3 months post-transplant thereafter until study closure.

Diphenhydramine

Intervention Type DRUG

30 to 60 minutes prior to the start of the infusion

* Claritin (Loratadine) 10mg by mouth or
* Benadryl (Diphenhydramine) 25 or 50 mg by mouth

Interventions

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Infliximab

A single dose, of 3mg/kg infusion

Intervention Type BIOLOGICAL

Methylprednisolone

500mg will be Initiated just prior to or at the initiation of transplant surgery and prior to Infliximab and thymoglobulin infusion

Intervention Type DRUG

Mycophenolate Mofetil

Administered at a target dose of 2000mg daily, as tolerated, until study closure

Intervention Type DRUG

Tacrolimus

Administered at a target dose of 0.1mg/kg BID, post-op, then adjusted to target trough levels of 8-12ng/ml during 1st 3-months post-op and finally adjusted to target trough levels of 5-8ng/ml until study closure

Intervention Type DRUG

Thymoglobulin®

Administered daily for 5 days with the intention of achieving a total dose of 4.5 to 6.0 mg/kg, as tolerated

Intervention Type BIOLOGICAL

Acetaminophen

30 to 60 minutes prior to the start of the infusion

* Tylenol, 600 to 1000mg by mouth or
* Suppository form

Intervention Type DRUG

Loratadine

30 to 60 minutes prior to the start of the infusion

* Claritin (Loratadine) 10mg by mouth or
* Benadryl (Diphenhydramine) 25 or 50 mg by mouth

Intervention Type DRUG

Placebo for Infliximab

A single dose is volume matched to Infliximab (250mL) infusion

Intervention Type BIOLOGICAL

Prednisone

Prednisone will be administered peri-operatively according to center practice. Prednisone should be gradually tapered to no less than 5 mg/day or 10 mg every other day by 3 months post-transplant thereafter until study closure.

Intervention Type DRUG

Diphenhydramine

30 to 60 minutes prior to the start of the infusion

* Claritin (Loratadine) 10mg by mouth or
* Benadryl (Diphenhydramine) 25 or 50 mg by mouth

Intervention Type DRUG

Other Intervention Names

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Remicade® Solu-Medrol MMF CellCept® FK-506 FR-900506 Prograf® Antithymocyte Globulin [Rabbit] Rabbit ATG Tylenol® Claritin® Benadryl

Eligibility Criteria

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Inclusion Criteria

1. Adult (\>18 years of age) male and female recipients (all races and ethnicities)
2. Subject must be able to understand and provide consent
3. Recipients of deceased donor kidney transplants (including re-transplants)
4. Negative crossmatch, actual or virtual, or a PRA of 0% on historic and current sera as determined by each participating study center
5. Donor kidneys from deceased donors and donors after cardiac death (DCD) with Kidney Donor Profile Indices (KDPI) ranging from ≥20 to \<95
6. Female participants of childbearing potential must have a negative pregnancy test upon study entry
7. Subjects must have a negative test result for latent tuberculosis (TB) infection (PPD, QuantiFERON, ELISPOT):

* Subjects who have a negative test result for latent TB infection within 1 year of transplant date are eligible for enrollment and no further action is required
* Subjects who have a negative test for latent TB infection that is greater than 1 year old are eligible for enrollment but are required to have a repeat test prior to transplantation.

Exclusion Criteria

1. Inability or unwillingness of a participant to give written informed consent or comply with study protocol
2. Recipients of living donor transplants
3. Presence of other transplanted solid organ (heart, lung, liver, pancreas, small intestines) or co-transplanted organ
4. Human immunodeficiency virus positive (HIV+) recipients
5. Epstein-Barr virus Immunoglobulin G (EBV IgG) negative recipients
6. Hepatitis B surface antigen positive kidney transplant recipients
7. Hepatitis B core antibody positive kidney transplant recipients
8. Hepatitis B negative kidney transplant recipients that receive transplants from Hepatitis B core antibody positive donor
9. Hepatitis C Virus positive (HCV+) patients who are either untreated or have failed to demonstrate sustained viral remission for more than 12 months after anti-viral treatment
10. Recipients with a previous history of active TB
11. Recipients with a positive test for latent TB infection (PPD, QuantiFERON, ELISPOT), regardless of previous therapy
12. Any severe infection at the time of transplantation.

--Note: Severe infection determination will be made by the local site investigator.
13. Severe congestive heart failure (NYHA functional class III or higher)
14. Subjects with a known hypersensitivity to any murine/ mouse proteins
15. Subjects with any history of receiving any anti-tumor necrosis factor (anti- TNF) products
16. Subjects in whom rabbit anti-thymocyte globulin (Thymoglobulin®) or infliximab might not be tolerated
17. Subjects with a white blood cell count less than 3000/mm\^3
18. Subjects with a platelet count less than 100,000/mm\^3
19. Subjects with systolic blood pressure \<100 mm/Hg
20. Subjects with symptomatic orthostatic hypotension or currently requiring Midodrine for blood pressure support
21. Subjects from, or who have traveled, to endemic areas with a history of active histoplasmosis or, with a chest x-ray consistent with previous active histoplasmosis (no serological testing required) :

--Endemic regions determined by site based on local standard of care.
22. Subjects currently or formerly residing in regions of the United States that are highly endemic for coccidioidomycosis, and who have a positive serologic test for coccidioidomycosis:

--Endemic regions determined by site based on local standard of care.
23. Recipients are excluded if the local site decides to treat the recipient with fluconazole because of diagnosis or suspicion of fungal infection the donor
24. Subjects that receive IVIG treatment within 3 months of transplant or planned intravenous immunoglobulin (IVIG) treatment peri-transplant
25. Use of an investigational agent within 4-weeks prior to study entry.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Clinical Trials in Organ Transplantation

NETWORK

Sponsor Role collaborator

Rho Federal Systems Division, Inc.

INDUSTRY

Sponsor Role collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Peter S. Heeger, MD

Role: PRINCIPAL_INVESTIGATOR

Icahn School of Medicine at Mount Sinai, Recanati Miller Transplant Institute

Donald E Hricik, MD

Role: STUDY_CHAIR

University Hospitals of Cleveland, Division of Nephrology & Hypertension

Locations

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University of Alabama at Birmingham

Birmingham, Alabama, United States

Site Status

University of California, Los Angeles

Los Angeles, California, United States

Site Status

University of California, San Francisco

San Francisco, California, United States

Site Status

Yale University

New Haven, Connecticut, United States

Site Status

Emory University

Atlanta, Georgia, United States

Site Status

University of Maryland

Baltimore, Maryland, United States

Site Status

Johns Hopkins University

Baltimore, Maryland, United States

Site Status

University of Michigan

Ann Arbor, Michigan, United States

Site Status

Washington University School of Medicine in St. Louis

St Louis, Missouri, United States

Site Status

Mount Sinai Medical Center

New York, New York, United States

Site Status

Cleveland Clinic

Cleveland, Ohio, United States

Site Status

University Hospitals of Cleveland

Cleveland, Ohio, United States

Site Status

University of Wisconsin

Madison, Wisconsin, United States

Site Status

University of Manitoba

Winnipeg, Manitoba, Canada

Site Status

Toronto General Hospital

Toronto, Ontario, Canada

Site Status

Countries

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United States Canada

References

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Wajih Z, Karpe KM, Walters GD. Interventions for BK virus infection in kidney transplant recipients. Cochrane Database Syst Rev. 2024 Oct 9;10(10):CD013344. doi: 10.1002/14651858.CD013344.pub2.

Reference Type DERIVED
PMID: 39382091 (View on PubMed)

Hricik DE, Armstrong B, Alhamad T, Brennan DC, Bromberg JS, Bunnapradist S, Chandran S, Fairchild RL, Foley DP, Formica R, Gibson IW, Kesler K, Kim SJ, Mannon RB, Menon MC, Newell KA, Nickerson P, Odim J, Poggio ED, Sung R, Shapiro R, Tinckam K, Vincenti F, Heeger PS. Infliximab Induction Lacks Efficacy and Increases BK Virus Infection in Deceased Donor Kidney Transplant Recipients: Results of the CTOT-19 Trial. J Am Soc Nephrol. 2023 Jan 1;34(1):145-159. doi: 10.1681/ASN.2022040454. Epub 2022 Oct 4.

Reference Type DERIVED
PMID: 36195441 (View on PubMed)

Provided Documents

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Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

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https://www.niaid.nih.gov/about/dait

Division of Allergy, Immunology, and Transplantation (DAIT)

https://www.niaid.nih.gov/

National Institute of Allergy and Infectious Diseases (NIAID)

https://www.ctotstudies.org/

Clinical Trials in Organ Transplantation (CTOT)

Other Identifiers

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U01AI063594

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NIAID CRMS ID#: 20678

Identifier Type: OTHER

Identifier Source: secondary_id

DAIT CTOT-19

Identifier Type: -

Identifier Source: org_study_id

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